Controls Of European Ancestry Research Articles

Inflammation and keratoconus: A comprehensive bidirectional Mendelian randomization analysis.

An increasing body of evidence supports the involvement of inflammation and immune responses in the occurrence and development of keratoconus (KC). However, the causal relationship between inflammatory factors and KC remains unclear. We employed a 2-way Mendelian randomization (MR) approach to investigate the interaction between KC and inflammatory factors. Instrumental variables for 41 circulating inflammatory regulators and 12 matrix metalloproteinases (MMPs) were selected from genome-wide association studies of European ancestry. Summary statistics for KC were obtained from a genome-wide association study comprising 2116 cases and 24,626 controls of European ancestry. The primary analytical method for assessing causality was the inverse-variance weighted method. Two additional MR methods (MR-Egger and weighted median) were employed to complement the inverse-variance weighted results. In addition, several sensitivity analyses were conducted to evaluate heterogeneity, horizontal pleiotropy, and stability. Our findings indicated that genetically predicted higher levels of macrophage inflammatory protein-1β (odds ratio = 1.126, 95% confidence interval: 1.029-1.232, P = .01) and MMP-13 (odds ratio = 1.211, 95% confidence interval: 1.070-1.371, P = .003) were positively associated with an elevated risk of KC. Conversely, genetically predicted KC was associated with increased levels of interferon-gamma, interleukin-4, and MMP-1. Our current study provided suggestive evidence supporting causal associations of macrophage inflammatory protein-1β and MMP-13 with the risk of KC. In addition, KC appeared to affect the expression of interferon-gamma, interleukin-4, and MMP-1.

The association between genetically predicted systemic inflammatory regulators and endometriosis: A bidirectional Mendelian randomization study.

Elevated levels of various cellular inflammatory markers have been observed in patients with endometriosis (EMs). However, a causal relationship between these markers and EMS has not been firmly established. This study aimed to assess the causality between cellular inflammatory markers and the onset of EMS using a bidirectional Mendelian randomization approach. Genetic associations for EMs were derived from the largest and most recent genome-wide association study (GWAS) involving 1937 EMS cases and 245,603 controls of European ancestry. Single nucleotide polymorphisms associated with 41 cellular cytokines and other systemic inflammatory regulators were identified from 8293 Finnish participants. Estimates were obtained using inverse-variance weighted, with sensitivity analyses conducted using MR-Egger, weighted median, and MR-PRESSO. Among the 41 systemic inflammatory regulators included in the analysis, none were associated with the risk of EMs. Elevated levels of IL-6 were associated with an increased risk of EMs (OR = 1.351, 95%CI = 1.015-1.797). Conversely, genetically predicted elevated levels of platelet-derived growth factor (PDGF-BB) were associated with a reduced risk of EMs (OR = 0.856, 95%CI = 0.742-0.987). Genetically predicted elevations in IL-6 may contribute to an increased risk of EMs, while elevated PDGF-BB levels appear protective, suggesting potential therapeutic targets for EMs. Other systemic inflammatory regulators seem unrelated to EMs risk, potentially representing downstream effects or consequences of shared factors between inflammation and EMs.

The combined effect of lifestyle factors and polygenic scores on age at onset in Parkinson’s disease

The objective of this study was to investigate the association between a Parkinson’s disease (PD)-specific polygenic score (PGS) and protective lifestyle factors on age at onset (AAO) in PD. We included data from 4367 patients with idiopathic PD, 159 patients with GBA1-PD, and 3090 healthy controls of European ancestry from AMP-PD, PPMI, and Fox Insight cohorts. The association between PGS and lifestyle factors on AAO was assessed with linear and Cox proportional hazards models. The PGS showed a negative association with AAO (β = − 1.07, p = 6 × 10–7) in patients with idiopathic PD. The use of one, two, or three of the protective lifestyle factors showed a reduction in the hazard ratio by 21% (p = 0.0001), 44% (p < 2 × 10–16), and 55% (p < 2 × 10–16), compared to no use. An additive effect of aspirin (β = 7.62, p = 9 × 10–7) and PGS (β = − 1.58, p = 0.0149) was found for AAO without an interaction (p = 0.9993) in the linear regressions, and similar effects were seen for tobacco. In contrast, no association between aspirin intake and AAO was found in GBA1-PD (p > 0.05). In our cohort, coffee, tobacco, aspirin, and PGS are independent predictors of PD AAO. Additionally, lifestyle factors seem to have a greater influence on AAO than common genetic risk variants with aspirin presenting the largest effect.

Causal associations between vitamin D and postpartum depression: A bidirectional mendelian randomization study

BackgroundPrevious epidemiological studies have reported associations between vitamin D and postpartum depression (PPD); however, the findings are inconsistent. This study employs bidirectional Mendelian Randomization (MR) to investigate the causal link between serum 25-hydroxyvitamin D [25(OH)D] levels and PPD. By utilizing genetic data from cohorts, this research aims to provide a more robust understanding of the potential relationship between vitamin D and PPD, addressing a critical gap in the current literature. MethodsA bidirectional MR analysis was conducted to investigate the genetic association between serum 25(OH)D and PPD using summary statistics extracted from GWAS datasets. The study included data from 15,668 patients with PPD and 376,755 healthy controls of European ancestry. The GWAS data for 25(OH)D were obtained from two studies within the UK Biobank, encompassing 496,946 and 79,366 participants. The primary analysis employed the inverse-variance weighted (IVW) method, while supplementary MR estimates were derived through the MR-Egger and weighted median (WME) methods. Furthermore, sensitivity analyses were implemented to ensure robustness and reliability, including Cochran's Q test, MR-PRESSO, MR-Egger intercept test, and the leave-one-out test. ResultsThe MR study revealed no substantial genetic correlation between serum 25(OH)D levels and PPD (OR = 1.065, 95%CI = 0.878–1.293, P = 0.522 for set A; OR = 0.978, 95 % CI = 0.669–1.430, P = 0.910 for set B). Additionally, in the reverse analysis, we did not observe a significant causal impact of PPD on serum 25(OH)D (OR = 1.001, 95%CI = 0.974–1.028, P = 0.951 for set A; OR = 1.011, 95%CI = 0.992–1.031, P = 0.261 for set B). The results obtained from MR-Egger and WME analyses concord with those derived from the IVW method. Conducting leave-one-out tests did not identify any single nucleotide polymorphism that might have influenced the MR results, confirming the robustness and reliability of the findings. ConclusionsThe results suggest the absence of a causal link between vitamin D concentrations and PPD. Inconsistent observations in previous observational studies may be attributed to residual confounding.

Exploring the protective association between COVID-19 infection and laryngeal cancer: insights from a Mendelian randomization study.

Viral infections have been implicated as a risk factor for laryngeal cancer. Given the possible effects of Corona virus disease 2019 (COVID-19) on the laryngeal tissue, we investigated the causal link between COVID-19 and laryngeal cancer using a two-sample Mendelian randomization (MR) approach. We utilized genetic data from the 5th Genome-wide association studies (GWAS) edition of the COVID-19 Host Genetics Initiative (published on January 18, 2021) and a large-scale laryngeal cancer GWAS comprising 180 cases and 218,612 controls of European ancestry. We applied inverse variance weighting, MR Egger, and weighted median methods to infer causality. We performed sensitivity analysis using the "leave-one-out" method to verify robustness. We found no evidence of a causal association between gene-predicted COVID-19 and laryngeal cancer [Odds ratio (OR)=0.24 (95% Confidence intervals (CI), 0.05-1.26), P=0.09]. However, we observed significant inverse associations between gene-predicted COVID-19 hospitalization [OR=0.51 (95% CI, 0.28-0.95), P=0.03] and severe patients [OR=0.62 (95% CI, 0.43-0.90), P=0.01] and laryngeal cancer. Notably, the study detected important genetic variants, such as rs13050728, that modulate the expression of interferon alpha receptor 2 (IFNAR2), indicating possible roles for immune response pathways in both COVID-19 and cancer. This study reveals a potential interaction between COVID-19 severity, genetic factors, and laryngeal cancer, underscoring the importance of investigating the immune response mechanisms in both conditions. These findings contribute to the understanding of the complex interactions between COVID-19 and laryngeal cancer and may guide future research on the role of immune response, particularly involving IFNAR2.

Genome-wide meta-analyses of restless legs syndrome yield insights into genetic architecture, disease biology and risk prediction

Restless legs syndrome (RLS) affects up to 10% of older adults. Their healthcare is impeded by delayed diagnosis and insufficient treatment. To advance disease prediction and find new entry points for therapy, we performed meta-analyses of genome-wide association studies in 116,647 individuals with RLS (cases) and 1,546,466 controls of European ancestry. The pooled analysis increased the number of risk loci eightfold to 164, including three on chromosome X. Sex-specific meta-analyses revealed largely overlapping genetic predispositions of the sexes (rg = 0.96). Locus annotation prioritized druggable genes such as glutamate receptors 1 and 4, and Mendelian randomization indicated RLS as a causal risk factor for diabetes. Machine learning approaches combining genetic and nongenetic information performed best in risk prediction (area under the curve (AUC) = 0.82–0.91). In summary, we identified targets for drug development and repurposing, prioritized potential causal relationships between RLS and relevant comorbidities and risk factors for follow-up and provided evidence that nonlinear interactions are likely relevant to RLS risk prediction.

Identification and correction for collider bias in a genome-wide association study of diabetes-related heart failure

Type 2 diabetes (T2D) is a major risk factor for heart failure (HF) and has elevated incidence among individuals with HF. Since genetics and HF can independently influence T2D, collider bias may occur when T2D (i.e., collider) is controlled for by design or analysis. Thus, we conducted a genome-wide association study (GWAS) of diabetes-related HF with correction for collider bias. We first performed a GWAS of HF to identify genetic instrumental variables (GIVs) for HF and to enable bidirectional Mendelian randomization (MR) analysis between T2D and HF. We identified 61 genomic loci, significantly associated with all-cause HF in 114,275 individuals with HF and over 1.5 million controls of European ancestry. Using a two-sample bidirectional MR approach with 59 and 82 GIVs for HF and T2D, respectively, we estimated that T2D increased HF risk (odds ratio [OR] 1.07, 95% confidence interval [CI] 1.04-1.10), while HF also increased T2D risk (OR 1.60, 95% CI 1.36-1.88). Then we performed a GWAS of diabetes-related HF corrected for collider bias due to the study design of index cases. After removing the spurious association of TCF7L2 locus due to collider bias, we identified two genome-wide significant loci close to PITX2 (chromosome 4) and CDKN2B-AS1 (chromosome 9) associated with diabetes-related HF in the Million Veteran Program and replicated the associations in the UK Biobank. Our MR findings provide strong evidence that HF increases T2D risk. As a result, collider bias leads to spurious genetic associations of diabetes-related HF, which can be effectively corrected to identify true positive loci.

Two genome-wide interaction loci modify the association of nonsteroidal anti-inflammatory drugs with colorectal cancer.

Regular, long-term aspirin use may act synergistically with genetic variants, particularly those in mechanistically relevant pathways, to confer a protective effect on colorectal cancer (CRC) risk. We leveraged pooled data from 52 clinical trial, cohort, and case-control studies that included 30,806 CRC cases and 41,861 controls of European ancestry to conduct a genome-wide interaction scan between regular aspirin/nonsteroidal anti-inflammatory drug (NSAID) use and imputed genetic variants. After adjusting for multiple comparisons, we identified statistically significant interactions between regular aspirin/NSAID use and variants in 6q24.1 (top hit rs72833769), which has evidence of influencing expression of TBC1D7 (a subunit of the TSC1-TSC2 complex, a key regulator of MTOR activity), and variants in 5p13.1 (top hit rs350047), which is associated with expression of PTGER4 (codes a cell surface receptor directly involved in the mode of action of aspirin). Genetic variants with functional impact may modulate the chemopreventive effect of regular aspirin use, and our study identifies putative previously unidentified targets for additional mechanistic interrogation.

Modifiable risk factors and inflammation-related proteins in polymyalgia rheumatica: genome-wide meta-analysis and Mendelian randomisation.

Polymyalgia rheumatica (PMR) is an age-related inflammatory disease of unknown cause. We aimed to identify potentially modifiable risk factors and therapeutic targets for preventing or treating PMR. We meta-analysed genetic association data from 8,156 cases of PMR (defined using diagnostic codes and self-report) and 416,495 controls of European ancestry from the UK Biobank and FinnGen. We then performed Mendelian randomization analyses to estimate the association between eight modifiable risk factors (using data from up to 1.2 million individuals) and 65 inflammation-related circulating proteins (up to 55,792 individuals), using the inverse variance weighted and pleiotropy robust methods. We identified three novel genome-wide significant loci in the IL1R1, NEK6 and CCDC88B genes and confirmation of previously described associations with HLA-DRB1 and ANKRD55. Genetically predicted smoking intensity (OR 1.32; 95%CI 1.08-1.60; p = 0.006) and visceral adiposity (OR 1.22; 95%CI 1.10-1.37; p = 3.10x10-4) were associated with PMR susceptibility. Multiple circulating proteins related to IL-1 family signaling were associated with PMR. IL-1 receptor-like 2, also known as IL-36 receptor (OR 1.25; p = 1.89x10-32), serum amyloid A2 (OR 1.06, 9.91x10-10) and CXCL6 (OR 1.09, p = 4.85x10-7) retained significance after correction for multiple testing. Reducing smoking and visceral adiposity at a population level might reduce incidence of PMR. We identified proteins that may play causal roles in PMR, potentially suggesting new therapeutic opportunities. Further research is needed before these findings are applied to clinical practice.

#1761 Whole-genome sequencing reveals contribution of rare and common variation to structural kidney and urinary tract malformations

Abstract Background and Aims Structural kidney and urinary tract malformations are the commonest cause of kidney failure in children and young adults. Targeted and whole-exome sequencing has identified over 50 monogenic causes for these phenotypically heterogeneous conditions but have largely focused on cohorts enriched for familial, syndromic, or consanguineous disease. We sought to better characterise the genetic architecture of these conditions using whole genome sequencing (WGS) data from the UK's 100 000 Genomes Project. Method 992 unrelated individuals with structural kidney and urinary tract malformations were assessed using the Genomics England clinical interpretation pipeline to determine a genetic diagnosis. Statistically robust case-control association testing was performed using WGS data from a subset of 813 patients and 25 205 ancestry-matched unaffected individuals seeking enrichment of common and rare single-nucleotide and structural variants (SNV/SVs) on a genome-wide, per-gene, and cis-regulatory element basis. Heritability analysis was carried out in 623 cases and 20 060 controls of European ancestry with polygenic risk scores (PRS) derived for each of the six phenotypes. The PUV-PRS was validated in an independent cohort of 77 patients from the AGORA data- and biobank and an additional 2 746 European controls. Results The overall diagnostic yield was 4.3% (43/992; Fig. 1) with age &amp;lt; 18 years (P = 2.0 × 10−4), family history (P = 7.5 × 10−3) and extra-renal features (P = 1.9 × 10−4) all independent predictors of a genetic diagnosis. The diagnostic yield was higher in cases with cystic kidney dysplasia (10.7%) or kidney anomalies (5.9%). HNF1B was the most frequently identified cause. Exome-wide rare variant analysis identified enrichment of SNV/indels affecting AUTS2 (P = 3.7 × 10−6), ARHGAP5 (P=6.0 × 10−6), known kidney malformation gene HNF1B (P = 6.1 × 10−6), and ZNF879 (P=7.0 × 10−6), all of which have been previously implicated in developmental and/or cancer pathways. An increased burden of rare SVs affecting HNF1B (P = 3.1 × 10−4) was observed. There was no evidence of enrichment for cis-regulatory element disrupting SVs. Genome-wide testing of 19 million common and low-frequency variants (minor allele frequency &amp;gt; 0.1%) did not detect any individual variants that were significantly associated in the total cohort, but together these variants were estimated to contribute to 23% (standard error 11%) of the heritability of kidney and urinary tract malformations in cases with European ancestry. Comparison of phenotype-specific PRS showed considerable overlap between kidney anomalies, cystic kidney dysplasia, obstructive uropathy and vesico-ureteric reflux but the polygenic contribution to PUV and bladder exstrophy was distinct (Fig. 2). A PUV-PRS consisting of 36, 106 variants was validated in an independent European cohort of 77 cases and 2 746 controls (empirical P = 1 × 10−4). Conclusion We show that non-Mendelian genomic factors are important for the pathogenesis of structural kidney and urinary tract malformations, supported by the observation that a minority of patients in this large unselected cohort have a monogenic diagnosis. In addition, a significant proportion of heritability can be attributed to common and low-frequency variation and there is overlap in the polygenic contributors to upper urinary tract malformations with distinct polygenic signatures relevant to PUV and bladder exstrophy. Larger cohorts of patients are needed to increase power to detect variants contributing to this heritability and identify biological mechanisms and pathways important for kidney and urinary tract development.

Risk loci involved in giant cell arteritis susceptibility: a genome-wide association study

Giant cell arteritis is an age-related vasculitis that mainly affects the aorta and its branches in individuals aged 50 years and older. Current options for diagnosis and treatment are scarce, highlighting the need to better understand its underlying pathogenesis. Genome-wide association studies (GWAS) have emerged as a powerful tool for unravelling the pathogenic mechanisms involved in complex diseases. We aimed to characterise the genetic basis of giant cell arteritis by performing the largest GWAS of this vasculitis to date and to assess the functional consequences and clinical implications of identified risk loci. We collected and meta-analysed genomic data from patients with giant cell arteritis and healthy controls of European ancestry from ten cohorts across Europe and North America. Eligible patients required confirmation of giant cell arteritis diagnosis by positive temporal artery biopsy, positive temporal artery doppler ultrasonography, or imaging techniques confirming large-vessel vasculitis. We assessed the functional consequences of loci associated with giant cell arteritis using cell enrichment analysis, fine-mapping, and causal gene prioritisation. We also performed a drug repurposing analysis and developed a polygenic risk score to explore the clinical implications of our findings. We included a total of 3498 patients with giant cell arteritis and 15 550 controls. We identified three novel loci associated with risk of giant cell arteritis. Two loci, MFGE8 (rs8029053; p=4·96 × 10-8; OR 1·19 [95% CI 1·12-1·26]) and VTN (rs704; p=2·75 × 10-9; OR 0·84 [0·79-0·89]), were related to angiogenesis pathways and the third locus, CCDC25 (rs11782624; p=1·28 × 10-8; OR 1·18 [1·12-1·25]), was related to neutrophil extracellular traps (NETs). We also found an association between this vasculitis and HLA region and PLG. Variants associated with giant cell arteritis seemed to fulfil a specific regulatory role in crucial immune cell types. Furthermore, we identified several drugs that could represent promising candidates for treatment of this disease. The polygenic risk score model was able to identify individuals at increased risk of developing giant cell arteritis (90th percentile OR 2·87 [95% CI 2·15-3·82]; p=1·73 × 10-13). We have found several additional loci associated with giant cell arteritis, highlighting the crucial role of angiogenesis in disease susceptibility. Our study represents a step forward in the translation of genomic findings to clinical practice in giant cell arteritis, proposing new treatments and a method to measure genetic predisposition to this vasculitis. Institute of Health Carlos III, Spanish Ministry of Science and Innovation, UK Medical Research Council, and National Institute for Health and Care Research.

Obesity and hypertension mediate the effect of education on deep intracerebral hemorrhage: A Mendelian randomization study

BackgroundEducational attainment (EA) as a stable indicator of socioeconomic status has been confirmed to affect intracerebral hemorrhage (ICH), but the mechanism relating EA and ICH is still unknown. AimTo explore the causal relationship between EA and ICH through a bidirectional and two-step Mendelian randomization (MR) study. MethodsUsing summary-level Genome-wide Association Study using GWAS data FROM CASES AND CONTROLS of European ancestry, we performed bidirectional and two-step MR analyses to explore the causal relationship between educational attainment and ICH to understand the mediating influence of risk factors in this process. We also carried out subgroup analysis according to the different sites (deep and lobar) of ICH. A set of sensitivity analyses were performed to test valid MR assumptions. ResultsBidirectional MR analysis consistently demonstrated a unidirectional causal effect, revealing that higher EA had a protective influence on ICH. Each additional 1-standard deviation (SD) increase in genetically predicted years of schooling was associated with a reduced risk of all ICH (inverse variance weighted (IVW) OR: 0.381 [95 %CI: 0.264–0.549]), deep ICH (OR: 0.334 [95 %CI: 0.216–0.517]), and lobar ICH (OR: 0.422 [95 %CI: 0.261–0.682]). The mediating effect of EA on all ICH was mediated via systolic blood pressure (SBP) (6.93 % [1.20–13.45 %]) and body mass index (BMI) (17.87 % [3.92–34.64 %]), and the mediating effect of EA on deep ICH was also mediated via SBP (7.85 % [1.55–15.07 %]) and BMI (18.63 % [4.02–36.26 %]). ConclusionThis study provides robust genetic evidence for supporting the protective effect of EA on ICH risk, with further evidence that the effect of EA on deep ICH is partially mediated through hypertension and obesity. Further validation is needed to ascertain whether these findings are applicable to other racial or general population groups.

No genetic causal association between periodontitis and ankylosing spondylitis: a bidirectional two-sample mendelian randomization analysis

BackgroundObservational studies that reveal an association between periodontitis (PD) and ankylosing spondylitis (AS) exist. However, observational research is prone to reverse causality and confounding factors, which make it challenging to infer cause-and-effect relationships. We conducted a two-sample Mendelian randomization (MR) study to examine the causal relationship between the genetic prediction of PD and AS.MethodsIn our study, single-nucleotide polymorphisms (SNPs) were defined as instrumental variables (IVs). The genetic association with PD came from the Gene-Lifestyle Interactions and Dental Endpoints (GLIDE) consortium, wherein 17353 cases of European ancestry and 28210 controls of European ancestry were included in this study. The genetic association with AS from the Neale Laboratory Consortium included 337,159 individuals from the United Kingdom, with 968 cases and 336,191 controls. MR analysis was mainly performed using the inverse-variance weighted (IVW) method. In addition, the robustness of the study findings was assessed using sensitivity, pleiotropy, and heterogeneity analyses.ResultsEighteen independent SNPs with P-values significantly smaller than 1 × 10− 5 were used as IV SNPs for PD, while 39 independent SNPs with P-values significantly smaller than 1 × 10− 5 were used as IV SNPs for AS. The results of the IVW method revealed no causal association between PD and AS (odds ratio = 1.00, 95% confidence interval: 0.99953 to 1.00067, P = 0.72). The MR-Egger method did not support the causal association between PD and AS. It is unlikely that horizontal pleiotropy distorts causal estimates based on sensitivity analysis. No significant heterogeneity was observed in the Q test. The ‘’leave-one-out’’ analysis demonstrated that the robustness of our results was unaffected by eliminating any of the IVs. Likewise, no significant causative effect for AS on PD was observed in the inverse MR analysis.ConclusionsThe study results do not support shared heritability or a causal association between PD and AS.

Genetically proxied interleukin-6 receptor inhibition increases risk of atopic dermatitis

BackgroundDermatitis has been reported after initiation of IL-6 receptor inhibitors (IL-6Ri), while genetic association studies of atopic dermatitis (AD) have implicated IL-6R pathway signalling. However, causality remains unclear. As indications for IL-6Ri expand, so do the clinical importance of determining whether there is mechanistic evidence linking it to AD. ObjectiveTo examine the association between IL-6Ri and risk of AD. MethodsTo genetically mimic IL-6Ri, we selected single nucleotide polymorphisms within or near the IL6R gene associated with C-reactive protein (CRP) at genome-wide significance among 343,524 individuals. Genetic data for AD were obtained from 10,788 cases and 30,047 controls of European ancestry. We used the inverse-variance weighted and pleiotropy-robust methods and examined genetic confounding using colocalization. Analyses were replicated using 13,473 AD Finnish cases and 2,385 East Asian cases. Results from three independent analyses were pooled by meta-analysis. ResultsGenetically proxied IL-6Ri was associated with increased risk of AD (OR 1.78 per 4.4 mg/l reduction in CRP; 95%CI 1.28, 2.48; p=6.5x10-4). Results were replicated using Finnish outcome data (OR 2.07; 95%CI 1.58, 2.72; p=1.57x10-7), and Eastern Asian datasets (OR 1.68; 95%CI 1.12, 2.54; p=0.013). Meta-analysis of three independent populations (OR 1.89; 95%CI 1.57, 2.28; p=2.68x10-11) showed no statistical evidence of heterogeneity (p=0.65). We found no statistical evidence for pleiotropy or genetic confounding. ConclusionThis genetic investigation provides consistent evidence, across independent multi-ancestry populations, that IL-6R signalling is causally implicated in AD susceptibility. Clinicians should remain vigilant for adverse effects resembling AD when using IL-6R inhibitors for immune-mediated inflammatory diseases.

The impact of neurocognitive and psychiatric disorders on the risk of idiopathic normal pressure hydrocephalus: A bidirectional Mendelian randomization study.

Neurocognitive and psychiatric disorders have been proved that they can comorbid more often with idiopathic normal pressure hydrocephalus (iNPH) than general population. However, the potential causal association between these disorders and iNPH has not been assessed. Thus, our study aims to investigate the causal relationship between them based on a bidirectional Mendelian randomization (MR) analysis. Random effects of the inverse variance weighted (IVW) method were conducted to obtain the causal association among the neurocognitive disorders, psychiatric disorders, and iNPH. Genome-wide association studies (GWAS) of 12 neurocognitive and psychiatric disorders were downloaded via the OpenGWAS database, GWAS Catalog, and Psychiatric Genomics Consortium, whereas GWAS data of iNPH were obtained from the FinnGen consortium round 9 release, with 767 cases and 375,610 controls of European ancestry. We also conducted the sensitivity analysis in these significant causal inferences using weighted median model, Cochrane's Q test, MR-Egger regression, MR Pleiotropy Residual Sum and Outlier detect and the leave-one-out analysis. For most of the neurocognitive and psychiatric disorders, no causal association was established between them and iNPH. We have found that iNPH (odds ratio [OR]=1.030, 95% confidence interval [CI]: 1.011-1.048, p=.001) is associated with increased risk for schizophrenia, which failed in validation of sensitivity analysis. Notably, genetically predicted Parkinson's disease (PD) is associated with increased risk of iNPH (OR=1.256, 95% CI: 1.045-1.511, p=.015). Our study has revealed the potential causal effect in which PD associated with an increased risk of iNPH. Further study is warranted to investigate the association between PD and iNPH and the potential underlying mechanism.

Unraveling the genetic basis of the causal association between inflammatory cytokines and osteonecrosis.

Previous studies have reported that the occurrence and development of osteonecrosis is closely associated with immune-inflammatory responses. Mendelian randomization was performed to further assess the causal correlation between 41 inflammatory cytokines and osteonecrosis. Two-sample Mendelian randomization utilized genetic variants for osteonecrosis from a large genome-wide association study (GWAS) with 606 cases and 209,575 controls of European ancestry. Another analysis included drug-induced osteonecrosis with 101 cases and 218,691 controls of European ancestry. Inflammatory cytokines were sourced from a GWAS abstract involving 8,293 healthy participants. The causal relationship between exposure and outcome was primarily explored using an inverse variance weighting approach. Multiple sensitivity analyses, including MR-Egger, weighted median, simple model, weighted model, and MR-PRESSO, were concurrently applied to bolster the final results. The results showed that bFGF, IL-2 and IL2-RA were clinically causally associated with the risk of osteonecrosis (OR=1.942, 95% CI=1.13-3.35, p=0.017; OR=0.688, 95% CI=0.50-0.94, p=0.021; OR=1.386, 95% CI=1.04-1.85, p = 0.026). there was a causal relationship between SCF and drug-related osteonecrosis (OR=3.356, 95% CI=1.09-10.30, p=0.034). This pioneering Mendelian randomization study is the first to explore the causal link between osteonecrosis and 41 inflammatory cytokines. It conclusively establishes a causal association between osteonecrosis and bFGF, IL-2, and IL-2RA. These findings offer valuable insights into osteonecrosis pathogenesis, paving the way for effective clinical management. The study suggests bFGF, IL-2, and IL-2RA as potential therapeutic targets for osteonecrosis treatment.

Associations of the circulating levels of cytokines with the risk of myeloproliferative neoplasms: a bidirectional mendelian-randomization study

ObjectiveIn the pathogenesis of myeloproliferative neoplasms (MPN), inflammation plays an important role. However, it is unclear whether there is a causal link between inflammation and MPNs. We used a bidirectional, two-sample Mendelian randomization (MR) approach to investigate the causal relationship between systemic inflammatory cytokines and myeloproliferative neoplasms.MethodsA genome-wide association study (GWAS) of 8293 European participants identified genetic instrumental variables for circulating cytokines and growth factors. Summary statistics of MPN were obtained from a GWAS including 1086 cases and 407,155 controls of European ancestry. The inverse-variance-weighted method was mainly used to compute odds ratios (OR) and 95% confidence intervals (Cl).ResultsOur results showed that higher Interleukin-2 receptor, alpha subunit (IL-2rα) levels, and higher Interferon gamma-induced protein 10 (IP-10) levels were associated with an increased risk of MPN (OR = 1.36,95%CI = 1.03–1.81, P = 0.032; OR = 1.55,95%CI = 1.09–2.22, P = 0.015; respectively).In addition, Genetically predicted MPN promotes expression of the inflammatory cytokines interleukin-10 (IL-10) (BETA = 0.033, 95% CI = 0.003 ~ 0.064, P = 0.032) and monokine induced by interferon-gamma (MIG) (BETA = 0.052, 95% CI = 0.002–0.102, P = 0.043) and, on activation, normal T cells express and secrete RANTES (BETA = 0.055, 95% CI = 0.0090.1, P = 0.018).ConclusionOur findings suggest that cytokines are essential to the pathophysiology of MPN. More research is required if these biomarkers can be used to prevent and treat MPN.

Causal associations between human gut microbiota and hemorrhoidal disease: A two-sample Mendelian randomization study.

Hemorrhoidal disease (HEM) is a common condition affecting a significant proportion of the population. However, the causal relationship between the gut microbiota and hemorrhoids remains unclear. In this study, we employed a Mendelian randomization (MR) approach to investigate the potential associations between them. In this study, the exposure factor was determined by selecting summary statistics data from a large-scale gut microbiome whole-genome association study conducted by the MiBioGen Consortium, which involved a sample size of 18,340 individuals. The disease outcome data consisted of 218,920 cases of HEM and 725,213 controls of European ancestry obtained from the European Bioinformatics Institute dataset. Two-sample MR analyses were performed to assess the causalities between gut microbiota and hemorrhoids using various methods, including inverse-variance weighting, MR-Egger regression, MR Pleiotropy Residual Sum and Outlier (MR-PRESSO), simple mode, and weighted median. Reverse MR analyses were performed to examine reverse causal association. Our findings suggest phylum Cyanobacteria (OR = 0.947, 95% CI: 0.915-0.980, P = 2.10 × 10 - 3), genus Phascolarctobacterium (OR = 0.960, 95% CI: 0.924-0.997, P = .034) and family FamilyXI (OR = 0.974, 95% CI: 0.952-0.997, P = .027) have potentially protective causal effects on the risk of HEM, while genus Ruminococcaceae_UCG_002 (OR = 1.036, 95% CI: 1.001-1.071, P = .042), family Peptostreptococcaceae (OR = 1.042, 95% CI: 1.004-1.082, P = .029), genus Oscillospira (OR = 1.048, 95% CI: 1.005-1.091, P = .026), family Alcaligenaceae (OR = 1.048, 95% CI: 1.005-1.091, P = .036) and order Burkholderiales (OR = 1.074, 95% CI: 1.020-1.130, P = 6.50 × 10-3) have opposite effect. However, there was a reverse causal relationship between HEM and genus Oscillospira (OR = 1.140, 95% CI: 1.002-1.295, P = .046) This is the first MR study to explore the causalities between specific gut microbiota taxa and hemorrhoidal disease, which may offer valuable insights for future clinical interventions for hemorrhoidal disease.

Exploring the causal relationship between Takayasu arteritis and inflammatory bowel disease using Mendelian randomization.

Takayasu arteritis (TA) and inflammatory bowel disease (IBD) are two distinct diseases; however, previous studies have reported many cases of IBD-TA coexistence. Additionally, the incidence of IBD in patients with TA is estimated to be significantly higher than the incidence in the general population. Therefore, the two diseases are anticipated to be linked. Mendelian randomization (MR) analysis assesses whether an exposure might causally affect an outcome by using genetic variants inherited randomly at conception, thereby reducing the impact of confounding and reverse causality. The present study aimed to investigate the potential causal relationship between TA and IBD using MR analysis. Two-sample MR analysis, in which TA and IBD were regarded as the exposure and outcome, respectively, was conducted to investigate whether the two diseases are causally related using the R TwoSampleMR package. Summary GWAS data of TA consisted of 516 Turkish cohorts and 462 controls, and 119 patients and 993 controls of European ancestry. Summary data of IBD was from a sub-study of the International Inflammatory Bowel Disease Genetics Consortium (IIBDGC) that comprised 31,665 cases and 33,977 controls of European ancestry. Additionally, separate MR analyses stratified by the two major subtypes of IBD, Crohn's disease (CD) and ulcerative colitis (UC), were performed. Various statistical tests, including the intercept of MR-Egger regression, funnel plots, Cochran's Q tests, and leave-one-out sensitivity analyses, were employed to assess the presence of heterogeneity and horizontal pleiotropy among single nucleotide polymorphisms (SNPs). In the primary analysis using the inverse-variance weighted (IVW) method, the risk of developing IBD for a patient with TA compared to a non-TA control increased 1.053 times (Odds Ratio (OR) = 1.053, P = 0.065). The MR-Egger method (OR = 1.025, P = 0.470) yielded results consistent with this null finding. However, both the weighted median method (OR = 1.038, P = 0.002) and the weighted mode method (OR = 1.051, P = 0.009) identified a significant harmful causal effect. The MR outcomes from separate subgroup analyses slightly diverged from those of IBD and TA. Specifically, for CD, three methods indicated that TA is a risk factor: IVW estimated the OR as 1.045 (P = 0.032), MR-Egger as 0.997 (P = 0.957), weighed median as 1.028 (P = 0.021), and weighted mode as 1.031 (P = 0.022), respectively. This study represents one of the initial investigations into the potential causal association between TA and IBD. With three MR methods, including the primary IVW approach, indicating a notable effect on TA on CD, our analysis findings offer some indication that TA could be a contributing risk factor for CD.

Genetic liability to elevated circulating IP-10, IFNγ and SCGFβ levels in relation to thoracic aortic aneurysm: A mendelian randomization study

Inflammation is associated with thoracic aortic aneurysm (TAA) but the effects of each circulating inflammatory factor on TAA remain unclear. In this study, we explored the relationship between circulating inflammatory factors and TAA risk using Mendelian randomization (MR) approach based on summary statistics from the latest genome-wide association study (GWAS) of 41 circulating inflammatory factors in 8293 Finns and a GWAS involving 1351 TAA cases and 18,295 controls of European ancestry. In univariable MR, higher interferon gamma-induced protein 10 (IP-10) levels, higher interferon gamma (IFNγ) levels and higher stem cell growth factor beta (SCGFβ) levels were associated with an increased risk of TAA (OR = 1.37, 95 % CI = 1.17–1.59, p = 7.42 × 10−5; OR = 1.43, 95 % CI = 1.19–1.74, p = 2.04 × 10−4; OR = 1.27, 95 % CI = 1.09–1.48, p = 2.40 × 10−3, respectively). In multivariable MR, the patterns of associations for the three cytokines remained adjusting for each other or smoking, but were attenuated differently with adjustment for other cardiovascular risk factors, especially for lipids and body mass index. Bidirectional MR approach did not identify any significant associations between cytokines and risk factors. Our results indicated that circulating cytokines may play mediation roles in the pathogenesis of TAA. Further studies are needed to determine whether these biomarkers can be used to prevent and treat TAA.